Alcohol abuse and dependence are global health concerns associated with numerous comorbidities. Hypoglycemia is a comorbidity particularly associated with binge-drinking. Under normal conditions glucose is the primary fuel for brain energy metabolism, so in hypoglycemia the brain relies increasingly on blood lactate, ketone bodies, and acetate, all of which cross the blood-brain barrier by the same monocarboxylic acid transporter. When drinking, the body converts alcohol to acetate, and rats are able to utilize the acetate, partially replacing glucose consumption. Studies of hypoglycemia in diabetes and in starvation show that the transport and utilization of monocarboxylic acids are enhanced by hypoglycemia and by elevations in monocarboxlyic acids. Therefore, we hypothesize that through repeated exposure to elevated acetate, ketones, lactate, and hypoglycemia, heavy drinkers who experience repeated episodes of hypoglycemia are more able to consume the acetate derived from ethanol than are light drinkers and non-drinkers. If the hypotheses of this project are supported, the fuel-generation aspect of alcohol may provide a novel award mechanism that promotes the continuation of heavy drinking and helps to prolong episodes of binge-drinking. The central question to be answered is this: Can heavy drinkers readily transport and utilize acetate for brain energy metabolism? A secondary question will be answered: For brain metabolism, do heavy drinkers more readily transport and utilize acetate than light/non- drinkers? These questions will be examined in three components during infusions of [2-13C]acetate. Measurements will be (1) brain acetate concentrations, (2) oxidize acetate more rapidly, and (3) blood-brain transport capacity of heavy drinkers relative to light/non-drinkers. The concentrations and rates of utilization acetate will be measured in 10 heavy drinkers and 10 light/non-drinkers during infusions of [2-13C]acetate. The measurements will utilize 13C MRS at 4 Tesla to detect the time courses of 13C-labeled acetate, glutamate, and glutamine in the brain. PUBLIC HEALTH RELEVANCE: Under most circumstances, people's brains derive nearly all their energy needs from the sugar glucose. Sometimes when people drink large quantities of alcohol, their blood sugar drops, particularly if they are not eating properly, and to survive, the brain must find alternatives to glucose. One alternative chemical that the brain can consume is acetate that the body forms from alcohol. In this study, we will determine if heavy drinkers are more able to use acetate as fuel for the brain. If they are, the possibility exists that heavy drinkers continue drinking not only for the known drug-effects of alcohol, but to provide sustenance for the brain when they do not eat properly, supporting an idea that nutrition is a key player in the ability to reduce heavy drinking or stop drinking alcohol.